CHICAGO, IL—Treating advanced melanoma patients with either a combination of the immunotherapy drugs nivolumab (Opdivo) and ipilimumab (Yervoy) or nivolumab alone significantly increases progression-free survival (PFS) compared with ipilimumab alone, according to new findings simultaneously presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the New England Journal of Medicine (2015; doi:10.1056/NEJMoa1504030).

Examining specific characteristics of each patient's tumor has also given researchers clearer understanding of which patients should receive the combination.

These initial findings from the phase III clinical trial confirm the results of the phase II trial, presented just weeks ago at the American Association of Cancer Research (AACR) Annual Meeting and published in New England Journal of Medicine (2015; doi:10.1056/NEJMoa1414428).

Jedd Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan-Kettering Cancer Center in New York, New York, designed and led the phase III randomized, double-blind trial, in which 945 patients with untreated advanced melanoma were randomized to receive ipilimumab alone, nivolumab alone, or a combination of the two.

Although this study was not designed for a formal statistical comparison between the nivolumab group and the combination group, exploratory analyses revealed more frequent responses and longer PFS in the combination group when compared with nivolumab alone. Patients receiving the combination experienced a median PFS of 11.5 months, while median PFS for patients receiving nivolumab alone was 6.9 months and ipilimumab alone was 2.9 months.

Of the 314 patients receiving the combination, 57.6% had an objective response, measured as a significant reduction in tumor size, versus 43.7% of the 316 receiving nivolumab alone and 19% of the 315 receiving ipilimumab alone.

"All the early preclinical and clinical work supported the idea that combining these two immunotherapy drugs could result in better outcomes for patients," said Wolchok. "We're encouraged by the progression-free survival data we're currently reporting. It is a testament to how drastically immunotherapy has altered the prognostic landscape for some advanced melanoma patients. Just 5 years ago, many of these patients would have been expected to live for only 7 months following diagnosis, but it's important to remember that overall survival data for this group is not yet available."

Adverse side effects such as diarrhea and increased lipase occurred in 55% of patients receiving the combination, and led about one-third of these patients to stop the regimen. About 16% of patients receiving nivolumab alone and 27% of patients receiving ipilimumab alone experienced side effects, with nearly 8% and 15% of patients discontinuing, respectively.

Ipilimumab and nivolumab are part of a class of drugs called immune checkpoint inhibitors, which unleash patients' immune system to attack their cancer. The immune system has several checkpoints in place to avoid an overreaction. Ipilimumab works by blocking the CTLA-4 checkpoint, a molecular brake that stops T cells from becoming fully and persistently activated. Similarly, nivolumab prevents the molecule PD-L1, expressed by tumors, from binding to T cells and deactivating them.

Notably in this trial, patients whose tumors expressed PD-L1 experienced a median PFS of 14 months regardless of whether they received the combination or nivolumab alone, but for patients whose tumors did not express PD-L1, the median PFS was longer on the combination (11.2 months) than on nivolumab alone (5.3 months).

"One of the biggest questions in the field of immunotherapy has been how to determine which patients will respond to immune-modulating drugs. Now we have another piece of data," said Wolchok. "A pathology test can identify patients whose tumors express PD-L1, and this information will help the patient and physician decide whether to use the combination or nivolumab alone, knowing the toxicity risks and the difference in PFS. However, if a patient's tumor does not express PD-L1, the data suggests it makes more sense to offer the combination. This understanding gets us closer to precision immunotherapy."

Wolchok designed this clinical trial on a napkin at the 2012 ASCO annual meeting, and did it before the data from the phase I trial were even presented.